Amyotrophic Lateral Sclerosis (ALS) is a severe progressive condition affecting 0.5-3 persons per 100,000 individuals. This degenerative disease is characterized by motor neuron death in the cortex, brainstem and spinal cord. Clinically the disorder presents as a disease of progressive muscle weakness and atrophy. The typical disease is insidious and invariably fatal. The neurofilament family consists of 3 genes, those encoding neurofilament light (NFL; 8p21), medium (NFM; 8p21) and heavy (NFH; 22q12.2) subunits. Neurofilament aggregation in the perikarya and proximal axons of motor neurons is a characteristic feature of the pathology of ALS. Whilst this does not constitute a causal link between NFs and ALS it is of note that over expression of altered or wild-type neurofilament in mice leads to a pathological phenotype resembling this disease. In collaboration with Dr Don Cleveland's laboratory at the University of California, San Diego and Dr Robert Brown's laboratory at Massachusets General Hospital we have undertaken a project to analyze the genetic contribution of neurofilament to ALS. We have sequenced the coding region of all three neurofilament genes in a series of 100 familial ALS cases, 100 sporadic ALS cases and 100 age matched neurologically normal conrol cases. We have identified 16 novel coding mutations in this series, present in all genes, although the majority are in the gene encoding the medium subunit. We confirmed these mutations by restriction digest, in the original series of 300 samples and, where applicable, in family members of patients carrying mutations. These data suggest that variability in the neurofilament genes does not play a major role in the genetic risk for ALS. We have also shown that a mutation (delta528) previously thought to cause Charcot Marie Tooth Disease type 2E is actually a rare variant which does not cause disease.